The transcription factor GABP – a member of a family of crucial gene-regulating proteins – is required to jump-start the process of cell division, according to research from The Warren Alpert Medical School of Brown University and Rhode Island Hospital. The work, published in Nature Cell Biology, uncovers a new way to control cell growth and points up potential targets for cancer treatments.

PROVIDENCE, R.I. [Brown University] — When cells go
about the business of dividing, they can get sidelined. Maybe there aren’t
enough nutrients. Maybe there aren’t the right signals to resume
multiplying. Either way, cells go quiet.

What can restart cell division – the process that drives
the development of embryos, the renewal of hair, skin and blood, and the
creation of cancer – is a single transcription factor called GABP,
according to new research from The Warren Alpert Medical School of Brown
University and Rhode Island Hospital.

The work, published online in Nature Cell Biology,
introduces a new pathway that can be manipulated to control cell growth. Since
cell growth is a fundamental biological process, the research may shed light on
everything from miscarriages to muscular dystrophy. The main application,
however, is cancer. Since a key characteristic of cancer cells is unchecked
growth, the research identifies potential targets for new treatments.

“As a scientist and a physician, I am tremendously
excited,” said Alan Rosmarin, M.D., an associate professor in the
Department of Medicine and the Department of Molecular Biology, Cell Biology and
Biochemistry at Brown and director of clinical oncology research for Lifespan,
Rhode Island’s largest health care system. “This discovery not only
adds to our basic understanding of cell division, it could lead to better cancer
drugs. And they’re needed. Cancer touches everyone.”

During the cell cycle, the four-phase process of cell division,
there is a period when the biochemical brakes are put on and cells become
inactive. Then the process is kick-started and cells move into the so-called S
phase, when DNA is duplicated. This is a critical juncture. If genes are missing
or broken, these alterations are passed on to the new cell – and could
result in disability or in diseases such as cancer.

So biologists are keenly interested in identifying the
accelerators that rev-up cell division. Ets transcription factors, a family of
gene-regulating proteins that are major players in embryonic and cancer
development, seemed obvious culprits. Rosmarin, a hematologist-oncologist,
studies one member of the Ets family called GABP. This transcription factor
helps make a variety of cells, including white blood cells. If those cells
develop abnormally, leukemia results.

But the exact function of GABP in the cell cycle wasn’t
known. Rosmarin wanted to find out. So he and members of his laboratory created
mice that carried a mutation – tiny DNA sequences were inserted into their
GABP-making gene. These DNA bits would serve as a time bomb of sorts, deleting a
critical piece of the gene when given a chemical signal.

From these mice, Rosmarin and his team grew fibroblasts –
common connective tissue cells – in a Petri dish with nutrient-rich serum
and watched them grow. When they detonated their time bomb, GABP was disrupted,
and the fibroblasts’ ability to divide was dramatically reduced. At the
same time, other genes known to restart cell division were unchanged.

The team confirmed GABP’s critical role in cell growth
another way. Simply forcing dormant cells to make GABP, they found, was enough
to rouse cells from their slumber and get them to grow again.

“So we’ve found a new pathway to control cell
growth,” Rosmarin said. “Now that we know a way to disrupt GABP and
stop division, there is the possibility that a drug can be made to do the same
thing in cancer cells.”

Zhong-Fa Yang, an instructor in medicine at Brown and a
postdoctoral research fellow at Rhode Island Hospital, was the lead author of
the journal article. Stephanie Mott, a Rhode Island Hospital research associate,
assisted with the experiments.

The National Heart, Lung and Blood Institute, the National
Center for Research Resources and the Herbert W. Saint ’49 Fund at Brown
University funded the work.

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